Novel Antibody Obliterates Psoriasis

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Secukinumab, a human anti-interleukin-17A monoclonal antibody was more effective than placebo or etanercept in two phase III double-blind studies in patients with moderate to severe plaque psoriasis.

The rates of infection were higher with secukinumab than with placebo and were similar to those with etanercept.

Treatment of longstanding moderate-to-severe plaque psoriasis with the monoclonal antibody secukinumab was associated with rapid and dramatic improvements, two large phase III clinical trials found.

In one study, known as ERASURE, improvements of 75% on the Psoriasis Area and Severity Index (PASI 75) were seen at 3 months in 81.6% of patients receiving 300 mg secukinumab and in 71.6% of those given 150 mg, compared with 4.5% of those randomized to placebo (P<0.001 for both), according to Richard G. Langley, MD, of Dalhousie University in Halifax, Nova Scotia, and colleagues.

In the second study, FIXTURE, PASI 75 responses at 3 months were reported for 77.1% of the 300 mg secukinumab group, 67% of the 150 mg group, 44% of those receiving etanercept (Enbrel), and 4.9% of those given placebo (P<0.001 for both etanercept and placebo), the researchers reported online in the New England Journal of Medicine.

"These are the best results of any of the treatments currently available for psoriasis," said study co-author Mark Lebwohl, MD, Sol and Clara Kest Professor and chairman of the department of dermatology at Icahn School of Medicine at Mount Sinai Hospital in New York City.

"The availability of this drug will dramatically change the treatment of psoriasis," Lebwohl told MedPage Today.

Secukinumab targets the pro-inflammatory cytokine interleukin (IL)-17A, which "acts as a master cytokine in the pathogenesis of psoriasis," Langley and colleagues explained.

To explore the efficacy and safety of blocking this cytokine in psoriasis, the investigators enrolled 737 patients from 88 centers for ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis) and 1,305 patients from 231 sites in FIXTURE (Full Year Investigative Examination of Secukinumab versus Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis).

Both studies had a 3-month induction phase, followed by a 40-week maintenance period, and a further 8 weeks of follow-up.

The induction phase in both studies involved 150 or 300 mg secukinumab given as subcutaneous injections at baseline, weekly for the first month, and monthly for the rest of the year. In FIXTURE, those randomized to etanercept were given subcutaneous injections twice weekly for the first 3 months and then once weekly for the remainder of the maintenance phase.

Patients' mean age was 45, and more than two-thirds were men. Average time since psoriasis diagnosis was 17 years, and baseline PASI scores were about 23 (out of a total of 72).

A co-primary endpoint along with PASI 75 was a score of zero (clear) or 1 (almost clear) on the physician's global assessment at 3 months.

In ERASURE, that endpoint was met by 63.5% and 51.2% of the 300 and 150 mg groups compared with 2.4% of the placebo group (P<0.001). In FIXTURE, 62.5% and 51.1% of the 300 and 150 mg patients met that endpoint, compared with 27.2% of those on etanercept (P<0.001) and 2.8% of those receiving placebo (P<0.001).

Substantial numbers of patients had even greater degrees of skin clearing. At 3 months, 59.2% and 39.1% of the 300 and 150 mg groups in ERASURE had PASI 90 responses, and 28.6% and 12.8% had PASI 100 responses.

In comparison, only 1.2% and 0.8% of patients on placebo had 90% and 100% improvement (P<0.001 for both).

PASI 90 responses in FIXTURE at 3 months were seen in 54.2% of the 300 mg group, in 41.9% of the 150 mg group, in 20.7% of the etanercept group (P<0.001), and in 1.5% of the placebo group (P<0.001).

In addition, PASI 100 responses were observed in 24.1% and 14.4% of the secukinumab groups and in 4.3% of the etanercept group (P<0.001).

Responses also were durable. In ERASURE, 80.5% of patients in the 300 mg group maintained the PASI 75 response through week 52, as did 72.4% of the 150 mg group. In FIXTURE, the responses were maintained by 84.3% and 82.2% of the secukinumab patients and by 72.5% of the etanercept patients.

"It's a remarkably effective drug, the response is very fast, and the durability of the response is very impressive," said Lebwohl, who is the president-elect of the American Academy of Dermatology.

An additional secondary outcome measure was the Dermatology Life Quality Index, which had changes of -11.4 and -10.1 in the 300 mg and 150 mg groups in ERASURE compared with -1.1 in the placebo group.

With regard to safety, the rates of infections for patients in the 300 and 150 mg secukinumab groups during the induction phase of FIXTURE were 26.7% and 30.9%, 24.5% with etanercept, and 19.3% for placebo.

A total of 4.7% of patients in the 300 mg group had mild or moderate candida infections, as did 2.3% of the 150 mg group. Among the etanercept patients, 1.2 had candida infections, one of which was severe.

"Interleukin-17A plays a key role in host defense, specifically in mucocutaneous microbial surveillance. Continued vigilance with respect to the potential for candida infection will be necessary for interleukin-17A inhibitors," Langley and colleagues cautioned.

"Neutropenia may also be of potential concern because of the reported role of interleukin-17A in the stimulation of granulopoiesis and neutrophil trafficking," they noted.

Grade 3 neutropenia also was reported in 1% of patients receiving secukinumab and in none of the patients treated with etanercept.

A limitation of the study was its short duration, which may not have been long enough for rare adverse events to emerge.

The study was supported by Novartis Pharmaceuticals.

The investigators disclosed financial relationships with Novartis and various other companies.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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